Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF) causes a spontaneously reversible increase in tight junction permeability. TNF was the only cytokine tested that produced this effect. The effect on transepithelial permeability proceeds in four distinct phases: 1) a 60- to 90-min delay from time of application of TNF, 2) a rapid decrease in transepithelial resistance, 3) a recovery of transepithelial resistance to control level within 1 h, and 4) a further increase of transepithelial resistance above control levels. The recovery of transepithelial resistance occurs with or without TNF in the culture medium. Different protein kinase inhibitors affected different phases of this overall process. The tyrosine kinase inhibitor genistein significantly blocked the TNF effect. Neither transcription nor protein synthesis was required for transepithelial permeability to increase, but were required for the recovery. After the tight junctions have opened at 2 h in response to TNF, a second application of TNF will not produce the effect again for at least 12 h. The tight junctions will, however, open in response to phorbol esters during this time frame. Electron microscopy studies using apically applied ruthenium red suggest that TNF action results in < 10% of the junctions having increased permeability at any given time during the resistance decrease. The role of epithelial barrier permeability changes in TNF action in vivo is discussed.
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PMID:Modulation of tumor necrosis factor-induced increase in renal (LLC-PK1) transepithelial permeability. 127 87

Calpactin I (annexin II) light chain gene messages were expressed in the DiFi and HT-29 human colon cancer cell lines, as well as in the diploid lung fibroblast cell line WI-38. However, expression of an approximately 1.0 kb transcript was stronger in DiFi and HT-29 cells than in WI-38 cells. The moderate to strong expression of such transcripts in DiFi and HT-29 cells indicates that the calcium binding protein, calpactin I, may be abundant in colon carcinoma cells. Calpactin I is the major substrate of pp60v-src, a tyrosine-specific protein kinase encoded by v-src, whose cellular homologue c-src also codes for a tyrosine kinase (pp60c-src), known to be activated in colon carcinomas and in cell lines derived from them (including HT-29). Abundance of calpactin I in such cells is consistent with the possibility that activation of the pp60c-src tyrosine kinase contributes to the origin of human colon cancers.
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PMID:Expression of the gene coding for the light chain of calpactin I (annexin II) in cell lines DiFi, HT-29, and WI-38. 128 33

p21c-ras plays a critical role in mediating tyrosine kinase-stimulated cell growth and differentiation. However, the pathways through which p21c-ras propagates these signals remain unknown. We report that in PC12 cells, expression of a dominant inhibitory mutant of ras, c-Ha-ras(Asn-17), antagonizes growth factor- and phorbol ester-induced activation of the erk-encoded family of MAP kinases, the 85-92 kd RSKs, and the kinase(s) responsible for hyperphosphorylation of the proto-oncogene product Raf-1. In addition, we find that expression of the activated ras oncogene is sufficient to stimulate these events. These data indicate that ras mediates nerve growth factor receptor and protein kinase C modulation of MAP kinases, RSKs, and Raf-1.
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PMID:ras mediates nerve growth factor receptor modulation of three signal-transducing protein kinases: MAP kinase, Raf-1, and RSK. 131 93

We have previously demonstrated that growth hormone (GH) promotes an increase in tyrosine kinase activity associated with the GH receptor. To gain insight into the role of GH-dependent tyrosine kinase activity in signaling by GH, we investigated the possibility that GH might stimulate MAP kinase, a serine/threonine/tyrosine kinase thought to be a common element in tyrosine kinase-initiated response cascades. Treatment of 3T3-F442A fibroblasts with 100 ng/ml GH results in a 3-6-fold increase in the ability of cell-free extracts to phosphorylate MAP-2 and myelin basic protein. GH-stimulated kinase activity is unaffected by heparin, H7, or cAMP-dependent protein kinase inhibitor peptide, partially reduced by staurosporin and inhibited by fluoride and calcium ions, indicating that the kinase is not protein kinase C or A, casein kinase, or a calcium/calmodulin-dependent protein kinase. Based on gel permeation chromatography, the molecular mass of the GH-stimulated MAP kinase is approximately kDa. Furthermore, anti-phosphotyrosine antibodies revealed the GH-dependent appearance of two phosphotyrosine-containing proteins in cell-free lysates of GH-treated cells that co-migrate with proteins recognized by anti-MAP kinase antibodies. The GH-dependent increase in MAP kinase activity displays a biphasic time course and is dependent on the concentration of GH applied to the cells. GH-dependent MAP kinase activity, partially purified by Mono-Q chromatography, is inactivated by treatment with alkaline phosphatase. Addition of H7 to the cells prior to the addition of GH has no effect, whereas addition of H8 increases MAP kinase activity in control cells with no effect in GH-treated cells, indicating that protein kinase C is unlikely to be an intermediary in the GH-dependent stimulation of MAP kinase activity. These findings indicate that signaling by GH in 3T3-F443A cells may, at least in part, utilize a kinase cascade similar to those that have been proposed for other membrane receptors with associated tyrosine kinase activity.
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PMID:Stimulation by growth hormone of MAP kinase activity in 3T3-F442A fibroblasts. 131 28

The protein kinase inhibitors staurosporine and K252A inhibit some of the cellular actions of nerve growth factor (NGF). To explore the molecular mechanisms involved, we test the ability of these agents to block one of the earliest cellular responses to NGF, protein tyrosine phosphorylation. Concentrations of 10-100 nM staurosporine and K252A inhibit NGF-dependent tyrosine phosphorylation in PC12 cells and inhibit trk oncogene-dependent tyrosine phosphorylation in trk-transformed NIH3T3 (trk-3T3 cells). In contrast, these compounds are without effect on epidermal growth factor (EGF)-stimulated tyrosine phosphorylation in PC12 cells. NGF-stimulated tyrosine phosphorylation of the pp140c-trk NGF receptor and tyrosine phosphorylation of pp70trk are also inhibited by similar concentrations of staurosporine and K252A, whereas tyrosine phosphorylation of the EGF receptor, insulin receptor, and v-src is not affected. Both staurosporine and K252A inhibit the autophosphorylation of pp70trk on tyrosine residues in an in vitro immune complex kinase reaction. Incubation of trk-3T3 cells with 10 nM staurosporine causes rounded transformed cells to revert to a normal flattened phenotype, whereas src-transformed cells are unaffected by this agent. These data suggest that staurosporine and K252A specifically inhibit the trk tyrosine kinase activity through a direct mechanism, probably accounting for the attenuation by these agents of the cellular actions of NGF.
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PMID:Inhibition of the cellular actions of nerve growth factor by staurosporine and K252A results from the attenuation of the activity of the trk tyrosine kinase. 131 57

The intracellular domain of the insulin receptor possesses activity as a tyrosine-specific protein kinase. The receptor tyrosine kinase is stimulated by insulin binding to the extracellular domain of the receptor. Previously, we have identified a patient with a genetic form of insulin resistance who is heterozygous for a mutation substituting Ile for Met1153 in the tyrosine kinase domain of the receptor near the cluster of the three major autophosphorylation sites (Tyr1158, Tyr1162, and Tyr1163). In this investigation, the Ile1153 mutant receptor was expressed by transfection of mutant cDNA into NIH-3T3 cells. The mutation impairs receptor tyrosine kinase activity and also inhibits the ability of insulin to stimulate 2-deoxyglucose uptake and thymidine incorporation. These data support the hypothesis that the receptor tyrosine activity plays a necessary role in the ability of the receptor to mediate insulin action in vivo. Furthermore, expression of the Ile1153 mutant receptor exerted a dominant negative effect to inhibit the ability of endogenous murine receptors for insulin and insulin-like growth factor I to mediate their actions upon the cell. This observation is consistent with previous suggestions that mutant receptors dimerize with wild type receptors, thereby creating hybrid molecules which lack biological activity. The dominant negative effect of the mutant receptor may explain the dominant mode of inheritance of insulin resistance caused by the Ile1153 mutation. Finally, the mutation inhibits the ability of insulin to stimulate receptor endocytosis. This may explain the normal number of insulin receptors on the surface of the patient's cells in vivo. Despite the presence of markedly elevated levels of insulin in the patient's plasma, the receptors were resistant to down-regulation.
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PMID:Substitution of isoleucine for methionine at position 1153 in the beta-subunit of the human insulin receptor. A mutation that impairs receptor tyrosine kinase activity, receptor endocytosis, and insulin action. 131 26

Two distinct isoforms of prostaglandin (PG) endoperoxide synthase (PGS) have been identified in rat ovarian tissues: rPGSi (mol wt, 70,000-72,000) is induced by FSH and LH in preovulatory follicles, whereas the other isoform (mol wt, 69,000) is not. Induction of rPGSi is associated with LH-stimulated increases in PG biosynthesis obligatory for ovulation. Because GnRH, like LH, can also stimulate the synthesis of PGs and ovulation in the rat, this study was undertaken to determine which isoform of PGS might be induced by GnRH, in what cell type, and by what intracellular pathways. Results show that GnRH at relatively low concentrations (10(-8)-10(-7) M) induced the same isoform of PGS (rPGSi) in the same cell type (preovulatory granulosa cells) and within the same 5- to 7-h time course as did LH. Unlike LH and FSH, GnRH did not cause a major increase in cAMP, nor did GnRH induce luteinization. The effects of GnRH on rPGSi in preovulatory follicles were not mimicked by known activators of protein kinase-C (phorbol myristate acetate, bryostatin, diacyglycerol, and (+/-)ionomycin). Epidermal growth factor (but not basic fibroblast growth factor or platelet-derived growth factor), which activates a receptor-associated tyrosine kinase, caused a small increase in rPGSi. Genistein, a selective inhibitor of tyrosine kinases, blocked GnRH and LH induction of rPGSi. Taken together these results suggest that the mechanisms by which GnRH and LH selectively induce rPGSi in granulosa cells of preovulatory follicles before ovulation may converge at some step within a cellular tyrosine kinase cascade. Furthermore, the mechanisms responsible for inducing rPGSi are distinct from those required for cellular luteinization.
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PMID:Induction of prostaglandin H synthase in rat preovulatory follicles by gonadotropin-releasing hormone. 131 86

The inhibition mechanisms of the epidermal growth factor (EGF) receptor tyrosine kinase and the cAMP-dependent kinase activities by erbstatin and its analogue, RG 14921, were studied by kinetic analysis. Both compounds were slow-binding inhibitors of the EGF receptor kinase. Erbstatin inhibited the EGF receptor kinase as a partial competitive inhibitor with respect to both ATP and the peptide substrate, suggesting that it binds at a site distinct from the ATP and peptide binding sites of the enzyme, and thus lowers the binding affinities of the enzyme for both substrates. In contrast, the analogue RG 14921 inhibited EGF receptor kinase activity as a non-competitive inhibitor with respect to both ATP and the peptide substrate. The distinct modes of inhibition by structurally related compounds suggest a dynamic and possibly extended structure of the catalytic center of the kinase domain of the receptor. Erbstatin and RG 14921 exerted similar effects on cAMP-dependent protein kinase activity. In this system, both compounds displayed potent inhibition and acted by a mode of competitive inhibition with respect to ATP and non-competitive with the peptide substrate.
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PMID:Inhibition kinetics and selectivity of the tyrosine kinase inhibitor erbstatin and a pyridone-based analogue. 131 62

Growth factors regulate cellular proliferation and differentiation by activating plasma membrane tyrosine kinase receptors and triggering a cascade of events mediated by intracellular signaling proteins. The mechanism underlying growth factor modification of cellular functions, such as gap-junctional communication (gjc), has not been established clearly. Addition of epidermal growth factor (EGF) to T51B rat liver epithelial cells resulted in the rapid activation of EGF receptor tyrosine kinase activity followed by a transient dose-dependent disruption of gjc. This change did not result from the gross disturbance of membrane gap junction plaques as measured by immunofluorescence microscopy, but instead correlated with markedly elevated phosphorylation of the connexin43 (cx43) gap junction protein, a profound shift to predominantly phosphorylated forms of cx43, and the appearance of a novel phosphorylated cx43 protein. These changes in cx43 phosphorylation involved only serine residues. On restoration of gjc, these alterations in cx43 phosphorylation reverted to the pre-EGF treatment state. Both events were inhibited by the serine/threonine protein phosphatase inhibitor, okadaic acid. Therefore, unlike the case for pp60v-src, EGF-induced disruption of gjc is not associated with tyrosine phosphorylation of cx43, but instead may result from phosphorylation of cx43 by activated intracellular signaling serine protein kinase(s).
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PMID:Epidermal growth factor disrupts gap-junctional communication and induces phosphorylation of connexin43 on serine. 132 98

Human cDNA clones encoding two novel proteins with a region strongly homologous to the tyrosine kinase domain of growth factor receptors, in particular of the Trk family, were obtained by a polymerase chain reaction-based approach. These proteins, Ror1 and Ror2, share 58% overall amino acid identity and a structure indicative of cell surface molecules. A secretion signal sequence and a transmembrane domain delimit the extracellular portion, which contains immunoglobulin-like, cysteine-rich, and kringle domains. The cytoplasmic portion contains the tyrosine kinase-like domain which (in Ror2) appears to be associated with protein kinase activity in vitro, followed by serine/threonine- and proline-rich motifs. Partial nucleotide sequences of the rat genes reveal striking evolutionary conservation of the proteins between human and rat. The level of expression of the rat genes is high in the head and body of early embryo and decreases dramatically after embryonic day 16. Based on these data, Ror1 and Ror2 appear to define a new developmentally regulated family of cell surface receptors for unidentified ligands.
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PMID:A novel family of cell surface receptors with tyrosine kinase-like domain. 133 94


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